Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2002-11-21
2004-03-16
Peselev, Elli (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S018500
Reexamination Certificate
active
06706865
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for preparing flavonoid compound useful for treating many kinds of diseases due to their aldose reductase inhibitory effect, active oxygen extinguishing effect, carcinogenesis promotion inhibitory effect, anti-inflammatory effect, and so on. More particularly, the present invention relates to a process for preparing astilbin, neoastilbin, isoastilbin, neoisoastilbin, cuersetin, smitilbin, engeletin, and analogous thereof.
BACKGROUND ART
Astilbin represented by the following formula (I-c):
is one of dihydroflavonol glycoside isolated from root of
Astilbe thunbergii
Miq., which is herbaceous perennial of saxifragaceous, as well as from the plant matter of Asmilaxylabra, Engelhardtia, Lyoniaovalifolia, Engelhardtiachrysolepis,
Chloranthus glarber
, Astilbe, microphylla, and so on. There has been reported that astilbin exhibits some important bioactivities such as aldose reductase inhibitory effect, active oxygen extinguishing effect, carcinogenesis promotion inhibitory effect, anti-inflammatory effect, and so on (Japanese Patent Publication Nos. 97/30984, 94/65074, 94/247851, and 94/256194), and therefore, astilbin is to be a very useful compound as anti-allergic drug or anticancer drug.
Astilbin of the formula (I-c) is a specific compound having two asymmetric carbon atoms at 2- and 3-positions of flavan skeleton, and rhamnose group is substituted at 3-position via O-glycosyl bound. A stereoisomer of astilbin, that is, neoastilbin, isoastilbin and neoisoastilbin, have same biological effects as those of astilbin, and further smitilbin or engeletin, analogous compound of astilbin, has improving effect for immune hepatic toxicity (
Planta Med.,
1999 February, 65(1): 56-59).
It has been known that astilbin or analogues thereof, including stereoisomeric compound, was obtained from plant matter (e.g.,
Astilbe thunbergii
Miq) by isolating and purification procedures. Further, the method for isomerising of astilbin and stereoisomer thereof using basic aqueous solution has only been reported (Yakugaku Zasshi, 1959, 80: 1202), and therefore, a chemical total synthesis of astilbin is not established up to now.
Hence the content of the objective compound in the plant matter is varied depending on the picking season, picking place and so on, and is very low, the isolating procedure from the plant matter is not available for industrial methods of producing said compound. Further, using the compound isolated from the plant matter as a medicine has some troubles due to the difficulties of separating from the analogous compounds and purifying the compound.
Accordingly, the object of the present invention is to provide a process for preparing a flavonoid compound having aldose reductase inhibitory effect, active oxygen extinguishing effect, carcinogenesis promotion inhibitory effect, anti-inflammatory effect, and so on. More particularly, the object of the present invention is to provide the industrial process for preparing astilbin and analogous thereof from the easily obtainable starting compound with short process and convenient means in high yield and high purity of the compound.
DISCLOSURE OF INVENTION
In order to solve the problems, therefore, the present inventors have found out that starting from readily available catechins, and reacting catechins with saccharides to obtain O-glycoside compounds then, oxidizing the C(4) position of flavonoid skeleton of obtained compounds to produce astilbin and analogous thereof in high yield by selectively process.
Accordingly, one aspect of the present invention is to provide a process for preparing a compound represented by the following formula (I):
wherein, R
2
is a substituted or unsubstituted phenyl group; R
7
is a hydrogen atom or a hydroxyl group; and n is an integer of 1 to 4,
which process is characterized in that reacting a compound of the following formula (II):
wherein, R
1
is a hydroxyl protecting group; R
2
and n have the same meanings mentioned above,
with a sugar compound of the following formula (III):
wherein, R
3
, R
4
and R
5
are independently each other, a hydrogen atom or a hydroxyl protecting group; R
6
is a hydrogen atom, a hydroxyl group or a protected hydroxyl group; and X is a halogen atom or an acyloxy group,
to produce a compound of following formula (IV):
wherein, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and n have the same meanings mentioned above,
then, conducting (a) or (b);
(a) oxidizing of 4-position of the flavonoid skeleton of the compound of the formula (IV) obtained above to produce a compound of the following formula (V):
wherein, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and n have the same meanings mentioned above,
or
(b) oxidizing of 4-position of the flavonoid skeleton of the compound of the formula (IV) to produce a compound of the following formula (VI):
wherein, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and n have the same meanings mentioned above,
subsequently, further oxidizing of 4-position of the flavonoid skeleton of the compound of the formula (VI) obtained above to produce a compound of the following formula (V):
wherein, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and n have the same meanings mentioned above,
and finally, removing the hydroxyl protecting group of the compound (V), obtained by the above methods (a) or (b), to produce the compound of the formula (I).
Specific aspect of the present invention, it is provided a process for preparing a compound represented by the following formula (I-a):
wherein, R
2
is a substituted or un-substituted phenyl group; R
7
is a hydrogen atom or a hydroxyl group.
More specific aspect of the present invention is to provide a process for preparing a compound represented by the following formula (I-b):
in which, the positions of hydroxyl groups at the flavonoid skeleton, and sugar derivative at 3-position are specified as mentioned above formula.
Still more specific aspect of the present invention is to provide a process for preparing a compound represented by the following formula (I-c):
that is, astilbin itself.
For the synthetic method of the compound of the formula (I) or the compound of the formula (V), the direct reaction of flavonoid compound having hydroxyl group at the 3-position and oxo group at the 4-position with the corresponding sugar derivative is thought as one method. However, the objective compound can't obtain by this method due to the interaction of hydroxyl group at the 3-position and oxo group at the 4-position of flavonoid skeleton.
According to the process of the present invention, the compound of the formula (I) or the compound of the formula (V) can be prepared from readily available compound and by industrial short process with high yield, and therefore, the present invention is superior one.
BEST MODE FOR CARRYING OUT THE INVENTION
In the present specification, the substitute for the substituted phenyl group represented by “R
2
” in the compound of formula (II) may be hydroxyl group; hydroxyl group protected by the protecting group of R
3
, R
4
, R
5
, or R
6
, described later; preferably straight or blanched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like; preferably straight or blanched alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, and the like; amino group; amino group protected by the protecting group of R
3
, R
4
, R
5
, or R
6
, described later; amide group; substituted amide group; lower acyl group such as acetyl, propionyl, tert-butyroyl, benzoyl and the like. In addition, number of the substitute and position of the substitute are not limited respectively.
In the formula (III), halogen atom represented by “X” is chlorine, bromine, iodine and fluorine; acyloxy group may be lower acyloxy group such as acetyloxy, propionyloxy, tert-butyroyloxy and the like, and aromatic acyloxy group such as benzoyloxy, toluyloxy and the like.
The present invention of process for preparing astilbin and analogous thereof is described in
Ohmori Ken
Suzuki Keisuke
Crowell & Moring LLP
Daiichi Suntory Pharma Co., Ltd.
Peselev Elli
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